Abstract The treatment of partial- and small full-thickness rotator cuff (RC) tendon tears is a considerable clinical challenge and lacks a ?gold standard? treatment. As surgical repair has not been shown to be more efficacious in patients with these tear types, physical therapy and corticosteroid injections are the most utilized treatment regimens. However, these small tears have been shown to continue to progress in size, causing redevelopment of symptoms, likely because conservative management does not facilitate structural healing of the tear and, therefore, is associated with risk for requiring future intervention. Given the high incidence of tear size progression with current management options, there exists an immediate need for a more efficacious treatment which not only improves clinical outcomes, but also induces structural and biological regeneration of the RC tendon. We propose a randomized, double-blind trial with 2-year follow-up to assess the efficacy of adipose-derived stromal vascular fraction (SVF) cells in the non-operative management of small RC tears. Patients treated with SVF cells will be compared to patients treated with a saline injection (n=24 each). Both groups will undergo standardized physical therapy. Our primary outcome measure will be imaging-based healing rates, which we will assess using 3-Tesla MRI at baseline (pre-treatment) and at 1 and 2 yrs of follow- up. Additionally, clinical outcomes will be compared between the two groups using both patient-reported outcome (PRO) measures and quantitative strength testing, collected at baseline, 3 months, 6 months, 1 yr, and 2 yrs of follow-up. PROs include the pain visual analog scale (VAS), Western Ontario RC index (WORC), and Patient Reported Outcome Measurement Information System (PROMIS) physical function (PF) upper extremity (UE) computer adaptive test (CAT). Finally, histological assessment of tissue cellularity, organization, and tenocyte anabolism will be performed with a minimally-invasive tendon biopsy, collected at baseline and at the 2-year follow-up. We expect to observe improved RC healing rates in the SVF group compared to the saline-treated group, based on 1- and 2-year follow-up imaging. By the final 2-yr follow-up, we expect to find complete healing in 50% of SVF-treated patients, compared to only 10% in the saline-treated patients. We anticipate that improved healing rates will correspond with superior PROs, and anticipate significantly greater improvements in shoulder strength, VAS pain, WORC, and PROMIS PF UE CAT in the SVF group at the 6- month, 1 and 2-year follow-up. Lastly, we expect the tendon biopsies from SVF-treated patients to exhibit a greater tenocyte number, higher collagen organization, higher type I-to-III collagen ratios, and greater tenomodulin expression, whereas biopsies from the saline-treated patients will exhibit disorganized, scar-like tissue with abnormal cellularity, low type I-to-III collagen ratios, and absence of tenomodulin expression. Identifying an efficacious, nonoperative, biologic treatment able to induce structural regeneration in small rotator cuff tears would represent a major shift in the treatment paradigm of patients with this injury.